R E S E A R C H Open AccessIncreased vulnerability of rural children on antiretroviral therapy attending public health facilities in South Africa: a retrospective cohort study Geoffrey F
Trang 1R E S E A R C H Open Access
Increased vulnerability of rural children on
antiretroviral therapy attending public health
facilities in South Africa: a retrospective cohort study Geoffrey Fatti1,2*, Peter Bock1,3, Ashraf Grimwood1, Brian Eley4
Abstract
Background: A large proportion of the 340,000 HIV-positive children in South Africa live in rural areas, yet there is little sub-Saharan data comparing rural paediatric antiretroviral therapy (ART) programme outcomes with urban facilities We compared clinical, immunological and virological outcomes between children at seven rural and
37 urban facilities across four provinces in South Africa
Methods: We conducted a retrospective cohort study of routine data of children enrolled on ART between
November 2003 and March 2008 in three settings, namely: urban residence and facility attendance (urban group); rural residence and facility attendance (rural group); and rural residents attending urban facilities (rural/urban
group) Outcome measures were: death, loss to follow up (LTFU), virological suppression, and changes in CD4 percentage and weight-for-age-z (WAZ) scores Kaplan-Meier estimates, logrank tests, multivariable Cox regression and generalized estimating equation models were used to compare outcomes between groups
Results: In total, 2332 ART-nạve children were included, (1727, 228 and 377 children in the urban, rural and rural/ urban groups, respectively) At presentation, rural group children were older (6.7 vs 5.6 and 5.8 years), had lower CD4 cell percentages (10.0% vs 12.8% and 12.7%), lower WAZ scores (-2.06 vs -1.46 and -1.41) and higher
proportions with severe underweight (26% vs.15% and 15%) compared with the urban and rural/urban groups, respectively Mortality was significantly higher in the rural group and LTFU significantly increased in the rural/urban group After 24 months of ART, mortality probabilities were 3.4% (CI: 2.4-4.8%), 7.7% (CI: 4.5-13.0%) and 3.1% (CI: 1.7-5.6%) p = 0.0137; LTFU probabilities were 11.5% (CI: 9.3-14.0%), 8.8% (CI: 4.5-16.9%) and 16.6% (CI: 12.4-22.6%),
p = 0.0028 in the urban, rural and rural/urban groups, respectively The rural group had an increased adjusted mortality probability, adjusted hazards ratio 2.41 (CI: 1.25-4.67) and the rural/urban group had an increased adjusted LTFU probability, aHR 2.85 (CI: 1.41-5.79) The rural/urban group had a decreased adjusted probability of virological suppression compared with the urban group at any timepoint on treatment, adjusted odds ratio 0.67 (CI: 0.48-0.93) Conclusions: Rural HIV-positive children are a vulnerable group, exhibiting delayed access to ART and an increased risk of poor outcomes while on ART Expansion of rural paediatric ART programmes, with future research exploring improvements to rural health system effectiveness, is required
Background
South Africa has the largest paediatric HIV epidemic and
the largest paediatric antiretroviral treatment (ART)
pro-gramme in the world [1] By mid-2009, an estimated
340,000 children younger than 15 years of age were living
with HIV infection [2], of whom approximately 70,000
were receiving ART [3] Paediatric ART outcomes
in South Africa have shown favourable short-term responses [4-7], with a recent cohort study involving
achieved virological suppression during the first three years of treatment [8] Despite the rapid scale up of ART programmes, marked inequities remain in access to early infant diagnosis and ART provision between different areas of the country [9]
* Correspondence: geoffrey.fatti@khethimpilo.org
1
Kheth ’Impilo, Green Square, 37 Hares Crescent, Woodstock, 7925, Cape
Town, South Africa
Full list of author information is available at the end of the article
© 2010 Fatti et al; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
Trang 2Limited information on the outcomes of children
managed in rural ART programmes is available in South
Africa A cohort from a single rural sub-district in the
province of KwaZulu-Natal demonstrated encouraging
short-term ART outcomes [10] However, a large
pro-portion of children developed virological failure and
major drug-resistant mutations on first-line ART in
another rural cohort [11] Most paediatric ART studies
in South Africa have included only urban children [4-8],
with no direct comparisons between outcomes in rural
population, however, lives in rural areas [12,13]
The prevalence of HIV in children and adults is as high
in rural as in urban areas [14], and certain rural districts
have reported extremely high infection rates, particularly
among women [15] A recent comparison of ART
out-comes between urban and rural children at three Zambian
sites demonstrated rural children having higher levels of
malnutrition at presentation and having higher mortality
rates while on treatment [16] Difficulties in providing
rural ART in sub-Saharan Africa include a lack of health
personnel, lack of diagnostic facilities, difficulty and
expense transporting medication to clinics, and a lack of
staff training in paediatric ART delivery [10,15,17]
In order to further examine the effectiveness of
pro-viding rural paediatric ART in low-income settings, the
aim of this study was to compare clinical,
immunologi-cal and virologiimmunologi-cal outcomes between rural and urban
children on ART in a large cohort from multiple public
health facilities in four provinces of South Africa
Methods
Study design, setting and participants
A retrospective cohort study of children enrolled on ART
was conducted at 44 routine public healthcare facilities
supported by Absolute Return for Kids South Africa
organization (NGO) that supports the scale up of ART in
public sector clinics in South Africa Seven rural and 37
urban sites that had electronic data collection systems
used for patient monitoring purposes were included in
the study Facilities were distributed across four
pro-vinces (Western Cape, KwaZulu-Natal, Eastern Cape and
Mpumalanga), with 12 facilities being secondary level
hospitals and 32 being primary healthcare clinics All
sites treated both adults and children
All ART-nạve children (<16 years) enrolled on ART
between 1 November 2003 and 31 December 2007 with
documented date of birth, gender and date of starting
ART, and who had initiated triple combination ART,
were included in the analyses Children were selected to
start ART according to the national Department of
Health guidelines [18] Briefly, children with modified
World Health Organization (WHO) clinical stage III or
stage IV disease, or a low CD4 cell percentage irrespec-tive of disease stage (<20% in children under 18 months
of age, or <15% if over 18 months old), or recurrent or prolonged hospitalization were eligible for ART
Additionally, children were required to have an identifi-able adult caregiver who could administer the medication First-line ART consisted of two nucleoside reverse tran-scriptase inhibitors (NRTIs) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI) for those aged older than three years or a protease inhibitor (PI) for those younger than three years PI-containing regimes were used for chil-dren who were exposed to perinatal nevirapine, and stavu-dine was used in preference to zidovustavu-dine when home refrigeration was available CD4 cell count and percentage was measured at ART initiation and at six-monthly inter-vals, and viral load was monitored six monthly on treat-ment Patients were followed up until 31 March 2008 or until the NGO exited from a site
Children were categorized into three groups defined
by their place of residence and ART facility attended, namely: urban residence and urban ART facility attended (urban group); rural residence and rural facility attended (rural group); and rural residents attending urban facilities (rural/urban group) The Global Rural-Urban Mapping Project population definitions were used to assign urban or rural categorization, in which settlements with a population of less than 5000 people are classified as rural [19] Population data were derived from the 2001 South African population census [20]
Outcomes and case definitions
Outcome measures were: death, loss to follow up (LTFU), virological suppression, and changes in CD4 cell percentage and weight-for-age-z-scores (WAZ) Fol-low-up time was censored at 24 months after starting ART LTFU was defined as no patient visit for three months after the last scheduled appointment was missed and viral load suppression as a viral load <400 copies/
ml Children who miss appointments would initially be traced by telephone and in certain cases, dependent on community health worker availability and if prior con-sent was obtained, a community health worker or dis-trict tracing team would visit the client’s house (tracing systems are, however, not standardized between sites) CD4 cell counts and viral load were measured by the National Health Laboratory Services using the Panleuco-gating method [21] and the Nuclisens HIV1 QT assay (bioMerieux, Marcy-Etiole, Rhơne), respectively
Data collection
Individual-level patient data were collected prospectively for routine monitoring purposes by designated site-based data capturers at each patient visit using Micro-soft Access databases, which were pooled on a quarterly
Trang 3basis to a central data warehouse using standard
operat-ing procedures Continual data cleanoperat-ing and quality
con-trol routines were implemented to enhance data validity
Missing data values were attempted to be retrieved by
hand searching paper-based patient records at facilities
The study was approved by the University of Cape
Town Research Ethics committee, reference number
368/2008
Statistical analysis
Children were categorized to age groups of <1 year, 1-2
characteristics between groups were compared using the
and Bonferroni tests, as appropriate Kaplan-Meier curves were fitted to
estimate mortality and LTFU from the programme The
logrank test was used to compare groups Multivariable
Cox proportional hazards regression was used to assess
group effect associated with death and LTFU until
24 months of ART, adjusting for baseline demographic
and clinical variables and accounting for heterogeneity
between individual site cohorts
For regression analyses, severe immunodeficiency was
defined according to WHO criteria [22]: CD4 percentage
than 12 months; CD4 percentage <20% or CD4 count
children between 36 and 59 months; and CD4 percentage
and older Due to the significant proportion of missing
values for baseline weight and WHO clinical stage, a
com-posite variable was created and named severe clinical
sta-tus, defined as a WAZ score of <-3 (severe underweight)
The influence of the availability of immunologic and
clinical status variables with mortality and LTFU were
assessed by considering missing values as a third category
to the initially binary variables When comparing groups,
the group with the lowest Kaplan-Meier estimates of
each outcome was selected as the comparative group
Subgroup analyses were additionally performed using
regression models to compare group effect by including
only children with all baseline variables being available
and substituting WHO clinical stage and WAZ-score
variables instead of severe clinical status
Multivariate generalized estimating-equation
popula-tion-averaged models were used to analyze group effect
on virological suppression, CD4 cell percentage increase
and WAZ-score increase until 24 months on ART,
adjusting for baseline clinical and demographic variables
Gender and age standardized z-scores for weight and
height were calculated using the Centres for Disease
Control 2000 growth reference standards [24] All
statistical analyses were performed using Stata version 9.2 (Stata Corporation, College Station, Texas, USA) Results
Database records for a total of 3358 children who started ART were screened for eligibility for the study
A total of 1026 were excluded for the following reasons:
572 were ART experienced; 352 commenced ART after
31 December 2007; and 102 had unavailable demo-graphic data Thus, 2332 ART-nạve children from seven rural and 37 urban facilities in four provinces were included in the analysis, with 605 children living in rural areas
There were 1727 (74.1%), 228 (9.8%) and 377 (16.2%) children in the urban, rural and rural/urban groups, respectively (Table 1) Children starting ART in the rural group were older, with a median age of 6.7 years compared with 5.6 years and 5.8 years (p = 0.0001) in the urban and rural/urban groups, respectively Rural group children had the lowest median baseline CD4 cell percentage (10.0%) compared with 12.8% and 12.8% (p = 0.0003; Kruskal-Wallis test) in the urban and rural/ urban groups, respectively
The rural group also displayed the highest proportion with severe immunodeficiency (79%; 95% CI: 73.6-84.8%;
p = 0.043) This group, however, displayed a trend toward less advanced baseline WHO clinical stage
69.0% in the urban and rural/urban groups, respectively,
p = 0.059), although no overall differences were found between groups in the proportions of patients with severe clinical status (p = 0.265) Children in the rural group had the lowest mean baseline WAZ score, being -2.06 (95% CI: -2.30 to -1.82; p <0.0001) and the highest proportion with severe underweight (25.9%; 95% CI: 19.3-33.4%; p = 0.002)
Seventy-nine children (3.5%) were documented as hav-ing started ART while takhav-ing antituberculous therapy, with no difference between groups The majority (75.2%) of children commenced NNRTI-based regimens; rural children had the lowest proportion starting PI-based regimens (6.3%; p < 0.0001), reflecting their older age and the different recommended initial regi-mens for older and younger children Urban children had a higher proportion starting regimens containing zidovudine (8.1%; p < 0.0001) instead of stavudine Overall programme retention in care and mortality after
24 months of ART was 84.5% (95% CI: 82.2%-86.6%) and 3.8% (95% CI: 2.9%-4.9%), respectively During the study period, 69 (3.0%) children died, with 44 (2.6%) children dying in the urban group, 14 (6.1%) in the rural group,
p = 0.011) After 24 months of ART, mortality probabilities were sig-nificantly higher in the rural group, being 3.4% (95% CI:
Trang 42.4-4.8%), 7.7% (95% CI: 4.5-13.0%) and 3.1% (95% CI:
1.7-5.6%) in the urban, rural and rural/urban groups,
respec-tively, logrank p = 0.0137 (Figure 1) Overall rates of
mortality peaked during the first six months of treatment,
with the highest rate in the rural group, being 5.4 (95% CI:
3.9-7.4), 11.4 (95% CI: 6.3-20.6) and 7.1 (95% CI: 3.9-12.8)
deaths per 100 person-years in the urban, rural and rural/
urban groups, repectively
Overall 179 (7.7%) children became lost to follow up,
125 (7.2%) in the urban group, 10 (4.4%) in the
rural group and 44 (11.7%) in the rural/urban group
(c2
p = 0.002) After 24 months of ART, the probability
of LTFU was almost two-fold higher among rural chil-dren travelling to urban treatment sites compared with those accessing care in rural areas, being 11.5% (95% CI: 9.3-14.0%), 8.8% (95% CI: 4.5-16.9%) and 16.6% (95% CI: 12.4-22.6%) in the urban, rural and urban/rural groups, respectively (logrank p = 0.0028) (Figure 2) For all groups, the instantaneous hazard of death was highest during the first six months of ART and levelled off over time on ART, while the instantaneous hazard of LTFU remained more constant over time
Table 1 Baseline characteristics of ART-nạve children beginning antiretroviral therapy
value
Group differinga (n = 2332) (n = 1727) (n = 228) (n = 377)
Weight-for-age z-score, mean (95% CI),
(n = 1572)
-1.51 (-1.59 to -1.44)
-1.46 (-1.54 to -1.38)
-2.06 (-2.30 to -1.82)
-1.41 (-1.60 to -1.22)
<0.0001 Rural Weight-for-age z-score < -3, n (%) 253 (16.1) 177 (15.0) 42 (25.9) 34 (14.9) <0.002 Rural Height-for-age z-score, mean (95% CI), (n = 359) -1.96 (-2.11 to
-1.82)
-1.91 (-2.01 to -1.75)
-2.26 (-2.70 to -1.82)
-1.96 (-2.26 to -1.27)
0.271 Severe clinical status, n (%), (n = 2057) 549 (26.7) 399 (25.9) 53 (27.0) 97 (30.3) 0.265
CD4 cell percentage; median (IQR), (n = 1425) 12.2 (7.0-18.0) 12.8 (7.1-19.0) 10.0 (6.0-14.2) 12.8 (6.3-18.1) 0.0003 Rural Absolute CD4 cell count (cells/mm 3 ); median
(IQR), (n = 1665)
271 (54-630) 301 (50-685) 212 (77-405) 206 (24-607) 0.0019 Urban Severe immunodeficiency, n (%), (n = 1772) 1285 (72.5) 933 (71.5) 172 (79.6) 180 (72.0) 0.045 Rural
TB treatment at ART initiation, n (%), (n = 2291) 79 (3.5) 51 (3.0) 8 (3.5) 20 (5.3) 0.090
Initial ART regimen, n (%), (n = 2280)
a
Indicates group differing significantly from the other groups.
b
10 children received d4t and ZDV, and did not receive an NNRTI or a PI.
WHO: World Health Organization.
Trang 5Table 2 shows the results of univariate and adjusted
regression models of baseline factors associated with
death and LTFU over 24 months of ART Forty-one
(1.7%) children were excluded from the final adjusted
models due to missing baseline tuberculosis treatment
information Children in the rural group had an
inde-pendently increased probability of mortality, aHR 2.41
(95% CI: 1.25-4.67; p = 0.009) in comparison with urban
children, after adjusting for baseline demographic and
clinical variables Severe clinical status, unavailable
clini-cal status, severe immunodeficiency and missing
base-line CD4 cell result were independently associated with
increased probabilities of mortality Children younger
than 12 months had an increased probability of
mortal-ity compared with children older than two years
Rural children travelling to urban facilities (rural/ urban group) had an independently increased probability
of LTFU, HR 2.85 (CI: 1.41-5.79; p = 0.004) compared with children accessing care in rural areas, after adjust-ing for baseline variables
The subgroup analyses selecting only children with all baseline variables available and using WHO stage and WAZ scores, instead of severe clinical status, included
1197 patients There were no statistically significant dif-ferences in baseline demographic or clinical variables between this subgroup and the whole cohort The prob-ability of mortality in the rural group remained indepen-dently increased, aHR 4.23 (95% CI: 1.36-13.2; p = 0.013) within this subgroup Children with WAZ scores
<-3 had an independently increased probability of mor-tality, aHR 4.93 (95% CI: 1.84-13.2; p = 0.001; univariate
HR 7.40 (95% CI: 3.12-17.6; p < 0.0001) in comparison with children with WAZ scores >-3 Children with WAZ scores between -3 and -1 were found not to have
an increased probability of mortality compared with children with WAZ scores >-1 (p = 0.561), and no deaths occurred among 231 children with WAZ scores
>0 There was no interaction between the effects of WAZ scores and the three groups on mortality
The probability of LTFU in the rural/urban group compared with the rural group remained independently elevated, aHR 3.56 (95% CI: 1.63-7.77; p = 0.001) in the subgroup There was no association between WAZ scores and LTFU (p = 0.50)
Among children with available viral load results, viro-logical suppression was good, being 80.8% (95% CI: 78.3-83.1%; n = 1036) and 83.1% (95% CI: 76.6-88.5%;
n = 66) after six and 24 months of ART, respectively The rural/urban group had a lower proportion of patients achieving virological suppression (74.6%; 95% CI: 68.4-80.1%; p = 0.038) at any time point up to 24 months after starting ART, compared with 80.4% (95% CI: 78.5-82.2) in the urban group and 79.6% (95% CI: 71.8%-86.0%) in the rural group Using a multivariate generalized estimating equation population-averaged model of virological suppression up to 24 months of ART adjusted for age, gender, clinical and immunologi-cal status, year of starting ART and initial regimen, the rural/urban group was associated with a reduced prob-ability of virological suppression compared with the urban group, (OR 0.67; 95% CI: 0.48-0.93; p = 0.017,
n = 1272 children) (Table 3) Children younger than two years had an independently reduced probability of virological suppression compared with children older than two years Duration of time on ART was not asso-ciated with virological suppression (p = 0.20)
After 12 months of ART, the median CD4 percentage increase was 12% (IQR: 7-17.6%) with no differences between the three groups (p = 0.88) The proportion of
Months on ART 6 12 18 24
Numbers on treatment:
Urban children 1174 780 493 190
Rural children 152 104 69 42
Rural/urban children 253 188 102 18
0.00
0.02
0.04
0.06
0.08
Months on ART
Rural
Urban
Rural/urban
Logrank p=0.014
Figure 1 Kaplan-Meier estimates of cumulative mortality
between rural and urban children.
Months on ART 6 12 18 24
Number at risk:
Urban children 1174 780 493 190
Rural children 152 104 69 42
Rural/urban children 253 188 102 18
0.00
0.05
0.10
0.15
Months on ART
Rural/urban
Rural Urban
Logrank p= 0.003
Figure 2 Kaplan-Meier estimates of cumulative loss to follow
up in rural and urban children.
Trang 6children with severe immunodeficiency at baseline was,
however, higher in the rural group (p = 0.043), and
remained higher up until the 12-month CD4 cell
mea-surement (p = 0.20) (Six-month meamea-surements were
41.8%, 57.7% and 36.5% in the urban, rural and rural/
urban groups, respectively, p = 0.027.)
Children accessing care in rural areas had significantly
lower baseline WAZ scores than children in other
groups, and as illustrated in Figure 3 this difference
per-sisted during treatment Multivariate analysis of WAZ
scores up to 24 months of ART, adjusting for baseline
demographic and clinical variables, revealed that children
in the rural group had independently reduced
on-treat-ment WAZ scores compared with children in the urban
group (co-efficient -0.42; 95% CI: -0.17 to -0.67; p =
0.001, n = 1756 children), i.e., over 24 months of
treat-ment, the adjusted mean difference in WAZ scores
mod-elled between rural and urban children was 0.4 points
(lower in rural children) There was no interaction
between the groups and duration of time on ART (p = 0.31), i.e., the rate of WAZ score increases on ART were equivalent between groups
The proportions of eligible patients with available results of scheduled six-monthly on-treatment labora-tory tests was significantly lower at rural health facilities than at urban facilities (Viral load result availability was 23%-46% and 58%-75% at rural and urban facilities, respectively; CD4 cell result availability was 54%-72% and 71%-84% at rural and urban facilities, respectively) Discussion
This study has directly compared ART outcomes in rural and urban children in South Africa, and indicates that children in rural areas have an increased risk of poor outcomes on ART Children receiving ART at rural facilities exhibited delayed access to ART, evi-denced by their older age, more advanced immunosup-pression, and greater degree of wasting when starting
Table 2 Factors associated with death and loss to follow up (LTFU) after 24 months of ART (n = 2291)a,b
Age
Severe clinical status
Immunodeficiency
Tuberculosis at ART start
Initial ART regimen
Urban/rural classification
a
Adjusted hazard ratios are adjusted for all variables displayed in the table.
b
41 (1.7%) of children were excluded due to missing baseline tuberculosis treatment information.
Trang 7treatment than their urban counterparts Rural Zambian
children in contrast were younger and had less advanced
immune suppression when starting treatment, although
they also displayed higher levels of malnutrition than
urban Zambian children [16]
Mortality in rural children
In data from low-income settings globally, reported
child mortality rates (including non-HIV-related
mortal-ity) are roughly one-third higher in rural children than
in urban children, being influenced by reduced
educa-tion, reduced access to safe water and sanitaeduca-tion,
reduced vaccine coverage and a lack of healthcare ser-vices [25] Rural childhood mortality in this dataset was, however, more than two-fold that of urban children, being similar to results from Zambia [16]
The reason for this is probably multi-factorial First, mortality is strongly associated with baseline CD4 cell percentage [26] Rural children had a reduced baseline CD4 cell percentage, and although median CD4 cell increases were equivalent between groups, a higher pro-portion of children at rural facilities had severe immu-nosuppression between months 0 and 6 of treatment, the period during which mortality rates were also the highest
Second, poor nutrition is an independent risk factor for mortality in HIV-infected children [27,28] and is common in high HIV-prevalence rural areas of South Africa [29] Adult ART programme mortality has also been reported to be higher in a rural South African set-ting than in urban setset-tings, and was associated with low baseline weight [30] The baseline nutritional status of rural children in this study was more impaired than that
of urban children and differences persisted during treat-ment, which likely contributed to the higher mortality Rural poverty, decreased access to high-protein food and greater environmental exposure to parasites are fac-tors that reduce rural nutritional status
Rural mortality remained elevated despite adjusting for available baseline clinical, nutritional and immunological variables, suggesting that other unmeasured factors were contributory causes Anaemia is an independent risk
Table 3 Generalized estimating-equation model of baseline factors associated with virological suppression until
24 months of ARTa
Age
Severe clinical status
Immunodeficiency
Urban/rural classification
a
Adjusted odds ratios are adjusted for all variables displayed, as well year of starting ART, initial regimen and duration of time on ART of 6-24 months.
Months on ART 0 6 12 18 24
Number of observations:
Urban children 979 946 572 373 180
Rural children 134 132 81 54 39
Rural/urban children 167 153 63 59 16
Figure 3 Changes in mean weight-for-age z-scores after
initiating ART in rural and urban childrena,b.aLimited to children
with measurement at ART start and at least one subsequent
measurement b Error bars are 95% confidence intervals.
Trang 8factor for mortality in HIV-infected children [27], and
has been found to be significantly more prevalent in
rural than in urban HIV-infected Indian children [31]
Serum haemoglobin was not recorded in the routine
monitoring data used in this study; however, poor
nutri-tional status suggests that anaemia may further
contri-bute to increased mortality in rural children
Site-based facility factors were not directly measured
in the study; however, the proportions of available
clini-cal and laboratory values may be used as a proxy for
site-based quality of care [32] There were increased
levels of unavailable baseline clinical and on-treatment
CD4 cell and viral load results at rural facilities
Unavail-able baseline clinical and immunological values were
also independently associated with increased risks of
mortality Further research of the quality of paediatric
ART care at rural facilities should therefore be
con-ducted to assess if it is equivalent to care at urban
facil-ities and to identify limitations
Loss to follow up in rural children attending urban
facilities
LTFU was significantly increased in rural children
mana-ged at urban facilities In Kwazulu-Natal Province, many
rural ART facilities at both district hospital and primary
healthcare level do not offer paediatric care, and children
need to travel long distances to urban ART centres to
access treatment Long transport distances and times, lack
of transportation, poor condition of roads, insufficient
transport money [33] exacerbated by rural poverty [34] are
barriers to the care of HIV-infected children in rural areas
Rural parents or carers on ART may attend a facility close
to home, but need to take their children to another,
dis-tant urban-based facility, which is further likely to increase
the risk of LTFU Children in the rural/urban group are
also less likely to have home-based adherence counsellor
visits, as counsellors are networked with the facilities and
do not support people long distances away
Poor virological response is an important factor
asso-ciated with disease progression and death, predisposes
to the development of drug-resistance, and reduces
future treatment options [35] Rural children travelling
to urban treatment centres had an approximately 30%
decreased probability of virological suppression
com-pared with urban children This is likely due to lower
ART adherence as a result of increased distances to
health facilities, decreased frequency of visits and
decreased or no contact with home adherence
counsel-lors In Limpopo Province, South Africa, rural children
with longer travel distances and decreased adherence
(self-reported and from pill counts) also demonstrated a
trend towards virologic failure [11]
Overall programme outcomes, however, compare very
favourably with results from other large cohorts in
low-income settings [8,23,26,36], and the results reinforce that good childhood ART outcomes on a broad scale are possible in sub-Saharan Africa
Improving clinical outcomes and increasing uptake of ART
Paediatric treatment is still provided mainly at hospitals due to the availability of paediatricians and related support and a shortage of clinicians at the primary healthcare level Lack of pharmacy staff at decentralized facilities is also a barrier, particularly for infants, as solutions currently need
to be dispensed by a qualified pharmacist Paediatric ART care can, however, be as effective at the primary healthcare level as hospital-based care, as has been demonstrated in the Western Cape in South Africa [37]
This data supports the process of shifting paediatric HIV care to the primary healthcare level, thereby increasing the number of service points and improving access and uptake of treatment, particularly in rural areas To achieve this, there needs to be a focus on ups-killing nurses and medical officers to initiate and main-tain children on treatment through training and mentoring, improving access to laboratories, expanding community support, subsidizing transport for compli-cated cases, and establishing clear referral pathways with outreach specialist support Furthermore, ensuring that all neonates exposed to HIV have HIV DNA polymerase chain reaction tests at their first vaccine visits at six weeks, and are followed up at 10 weeks with urgent referral to an ART facility if found to be positive will likely lead to decreased early childhood mortality [38]
Strengths and limitations
The strengths of this study are that pooled data from a large number of patients and sites in different settings were used, and individual-level data was collected pro-spectively enabling exploration and adjustment of patient factors associated with outcomes This study is a retrospective analysis using routine data with its inher-ent limitations; however, it is likely to be indicative of the situation at an operational level Missing viral load results were prevalent, particularly at rural sites, which may bias viral suppression estimates; the proportion of available results was, however, higher than those from a number of other sub-Saharan ART programmes [39] All children were eligible for laboratory testing at six-monthly intervals, irrespective of clinical condition in accordance with South African national guidelines, and all available results were due to be captured in the data-base Therefore, any bias due to missing laboratory results is expected to be non-systematic
The sites included were all supported by an NGO, and
it is possible that the outcomes may not be easily gener-alizable to non-NGO-supported government health
Trang 9facilities Adherence determination data (such as pill
counts) was not collected as they do not form part of
the routine data captured for public-sector ART patients
in South Africa A proxy measure of adherence, such as
pharmacy refill data, was not included in this study It is
possible that ascertainment of death was more complete
at rural (smaller) than urban (larger) sites However, as
the vital status of patients LTFU in this study was not
traced, this could not be accurately determined In
addi-tion, data on distance travelled to clinics and relocations
were not available Socio-economic factors may
addi-tionally be associated with mortality, but it was not
pos-sible to collect socio-economic data for the whole
cohort for this study and it was not possible to include
this variable in analyses
Conclusions
Rural HIV-infected children are a vulnerable group, and
providing care in rural areas poses significant challenges
Most studies investigating the outcomes of ART
pro-grammes involve urban children, and almost
three-quar-ters of children in this study lived in urban areas Future
research of rural paediatric ART programmes is important
and should examine the mechanisms underpinning the
observed vulnerability, explore cost-effective
improve-ments and efficiency in health systems, and determine the
degree to which HIV-infected children and their families
in rural settings require additional nutritional, healthcare
and social support
Acknowledgements
Early results of this study were presented at the 5thInternational AIDS
Society Conference on Pathogenesis, Treatment and Prevention in Cape
Town, South Africa, on 12-22 July 2009.
The authors wish to acknowledge Sarah Wampold, Vasigan Pillay, Esca
Scheepers, Kheth ’Impilo colleagues, PEPFAR, Absolute Return for Kids, and
the departments of health from the Western Cape, Eastern Cape,
KwaZulu-Natal and Mpumalanga, without whom this work would not have been
possible.
Author details
1 Kheth ’Impilo, Green Square, 37 Hares Crescent, Woodstock, 7925, Cape
Town, South Africa.2Lung Clinical Research Unit, University of Cape Town
Lung Institute, George Street, Mowbray, Cape Town, South Africa 3 Primary
Healthcare Directorate, University of Cape Town, Groote Schuur Hospital,
Observatory, Cape Town, South Africa 4 Paediatric Infectious Diseases Unit,
Red Cross Children ’s Hospital, School of Child and Adolescent Health,
University of Cape Town, Klipfontein Road, Rondebosch, Cape Town, South
Africa.
Authors ’ contributions
GF, PB and BE designed the study GF analyzed the data All authors
interpreted the data All authors contributed to the writing of the
manuscript, and all authors approved the manuscript for publication.
Competing interests
The authors declare that they have no competing interests.
Received: 13 August 2010 Accepted: 25 November 2010
Published: 25 November 2010
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doi:10.1186/1758-2652-13-46
Cite this article as: Fatti et al.: Increased vulnerability of rural children on
antiretroviral therapy attending public health facilities in South Africa: a
retrospective cohort study Journal of the International AIDS Society 2010 13:46.
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